Dialkylaminopropyl ethers of benzhydrol



Patented Sept. 23, 1947 mm ETHEBS OF BENZHYDBOL George Rievesobl, In, Grosse Pointe Woods, Mich assignor to Parke, Davis & Company, Detroit, 1 11011.. a corporation of Michigan No Drawing. Application April8, 1947, Serial No. 139,985

9(ilaims.

This invention relates to their acid addition salts and to methods for obtaining the same. More specifically, the invention relates to basically substituted benzhydryl ethers and their acid addition salts. The free bases of the basically substituted benzhydryl ethers oi! the invention have the iormula,

CHOCHICHiCHiI Q m where R1 and R: represent the same or diflerent alkyl radicals containing not more than 4 carbon atoms.

The compounds or the present invention may be obtained as a free base having the formula given above or as acid addition salts of the base with inorganic or organic acids. Some examples oi! the salts which may be prepared by the methods hereinafter described are the hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate. acetate, citrate, oxalate, succinate, benzoate, tartrate, phthalate, maleate, oleate and the like.

The basically substituted benzhydryl ether compounds may be prepared by several different processes. For example, these compounds may be prepared by the condensation oi. a benzhydryl halide with a -y-dialkylaminopropanol. The conamino ethers and 4 densation of these two reactants may be carried out by several different methods, e. g. it may be efiected in the presence or absence of an acidbinding agent or with or without a solvent. Another method for preparing these compounds consists in reacting an alkali metal salt of benzhydrol with a y-dalkylaminopropyl halide or, if desired, the reactants may be interchanged and an alkali metal salt of a 'y-dialkylaminopropanol reacted with a benzhydryl halide. A further method of preparation consists in reacting a 'y-halo propyl benzhydryl ether with an appropriate dialkylamine.

The free bases and the acid addition salts of the basically substituted benzydryl ethers are powerful anti-histamine agents. They are also useful in preventing smooth muscle spasms induced by histamine, acetyl choline or barium chloride. Another property of these compounds is that they inhibit gastric secretion which has been induced either by meal or histamine stimulus. The new parenterally, rectally or as a vapor or mist. They 11nd particular use in humans for treatment orallersic conditions (asthma, urticaria, histamine cephalagia and anaphylactic shock) and smooth muscle spasms (biliary spasm anddysemenorrhea). For example, the compound shown in Example 1, 'y-diethylaminopropyl benzhydryl ether hydrochloride, may be administrted to humans orally in a dosage of to 800 m8. per day and intravenously in a dosage of 10 to 100 mg. per day. However. because oi the high activity or this compound and the other compounds oi this invention, it has been found that a dosage of mg. per day orally or 20 mg. per day by the intravenous route is usually sufllcient in the treatment of smooth muscle spasms and most allergic conditions.

This application is a continuation-in-part of my copending application, Serial No. 531,639, filed April 18, 1944, now Patent No. 2,421,714, issued June 3, 1947.

The invention is illustrated by the foliovia ing examples.

Example 1. -Diethylamimpmml benzhydryl ether onion:

CHOCH:CH:CH:N

CHiCHt 'C./4.5 mm. (bath temperature 250- 90" 0.); yield Theiree base can be converted to the hydrochloride salt by dissolving it in dry ether and treating the resulting solution with an excess of dry hydrogen chloride gas. The hydrochloride salt which separates from the solution is collected and purified by recrystallization from isopropanol-acetone or ether mixture. In some instances diiiiculty is encountered in crystallizing this hydrochloride salt due to the fact that it contains a small amountof water. This may be overcome by evaporating the ether-salt mixture to dryness and then placing it in vacuo over phosphorus pentoxide for about one day. The dry material thus obtained is taken up and recrystallized from isopropanol.

Example 2. v-Dimethylaminopropyl benzhydn/l 247 g. of benzhydryl bromide is added to a refluxing solution or 206 g. of 'y-dimethylaminopropanol in 100 cc. of xylene. Aiter the addition a has been completed. the mixture is refluxed about fifteen hours. cooled and the lower layer consisting of the hydrobromide salt or -y-dimethylaminopropanol drawn off. The xylene is distilled from the upper layer in vacuo and the cool residue dissolved as completely as possible in dilute hydrochloric acid. After extraction of insoluble material with ether, the acidic aqueous solution is made alkaline with N sodium hydroxide and the desired free base extracted with ether. The ether extracts are dried, the ether evaporated and the residue distilled under a pressure of about 3 mm. of mercury to obtain the free base in pure form.

If desired, the free base can be converted to the hydrobromide salt by dissolving it in isopropanol and adding an excess of an isopropanol solution of hydrogen bromide. Ether is added and the crude salt which separates collected and purlfled by recrystallization from isopropanol.

By substituting an isopropanol solution of hydrogen chloride for the hydrogen bromide solution used in the preparation of the hydrobromide salt, one obtains the hydrochloride salt or 'y-dimethylaminopropyl benzhydryl ether as a white crystalline solid.

Example 3. -Di-n-butylaminopropz/l benzhy- CHICHiCHICHI CHO CHICHICH2N/ CHrCHaCHzCH:

23 g. of sodium wire is added to a solution of 200 g. of 'y-di-n-butylaminopropanol in 500 cc. of dry benzene and the resulting mixture stirred and heated until all the sodium has reacted with the amino alcohol. A solution of 247 g. of benzhydryl bromide in 300 cc. of dry benzene is added slowly to the rapidly stirred and refluxing mixture and after the addition has been completed the mixture is refluxed for flfteen hours. The mixture is cooled, washed with several portions of water to remove the sodium bromide and the organic layer distilled in vacuo to remove the benzene and excess amino alcohol. The residue is treated with dilute hydrochloric acid and extracted with ether. The ether extracts are discarded and the aqueous solution made alkaline with 20% sodium hydroxide solution in the cold. The free base is extracted with ether, the ether extracts dried and the ether distilled. The residue is distilled in vacuo (about 2 to 3 mm. oi mercury) to obtain the pure free base of the desired v-di-nbutylaminopropyl benzhydryl ether as a very pale yellow, viscous liquid.

If desired, the free base can be converted to a hydrohalide salt by dissolving it in ether and treating the resultant solution with an e cess of 4 the gaseous hydrohalide. The crude salt which separates is collected and purified by recrystallization from isopropanol-aeetone or ether mixture. some further examples or the compounds 0! the invention which can be prepared by the hereinbeiore described methods have the iollowlng i'ormulae for the free base:

CHICHICHI CHOCHQCHICHIN CHsCHsCHI CH: CHOCHaCHICHsN O CHaCHs 3\ CHOCHICHICHIN/ O CHCH:

Attention is called to the fact that compounds somewhat related to those clalmed herein are described and claimed in my copending applications as follows: Serial No. 531,839, flied April 18. 1944, now Patent No. 2,421,714 issued June 3, 1947; Serial No. 640,685, flied January 11, 1946; Serial No. 640,688, flied January 11, 1946; Serial No. 640,687, flied January 11, 1946; Serial No. 660,406, filed April 8, 1946; Serial N0. 688,424, flied August 5, 1948; Serial No. 688,425, flied August 5, 1946; Serial No. 688,428, flied August 5, 1946; Serial No. 688,427, filed August 5, 1946; Serial No. 151,983, flled June 2, 1947; Serial No. 751,- 984, filed June 2, 1947; and Serial No. 751,985, filed June 2, 1947. Other copending applications describing and claiming certain novel processes for the preparation of the compounds herein claimed and others somewhat related thereto are as follows: Serial Nos. 888,420, 688,421, 688,422 and 6 8, all flled August 6, 1946.

What I claim as my invention is:

1. A compound of the class consisting of a free base and its salts, said free base having the formula,

CH0 OHrCHaCHrN/ where R: and R: are each alkyl containing not more than four carbon atoms.

2. A compound having the formula,

CHO CHICHQCHIN where R1 and R: are each alkyl containing not more than four carbon atoms.

3. A salt 01' a compound having the iollowing formula for the free base.

CHOCHsCHaCHlI/ where R1 and R: are each alkyl containing not more than four carbon atoms.

5 6 4. The lwdrochloride salt of a. compound hav- 5. A salt of qdiethyiaminopropyl benzhydryl ing the ioiiowing formula. for the free base, ether.

6. The hydrochloride salt of 'y-diethylamino- Q prgpyl benzhydryl ether.

5 A salt of 'y-dimethyiaminopropyl benzhycnocmcmcmi ml amen 7 Q a. The hydrochloride salt of 'y-dimethylaminopropyl benzhydryl ether. where R1 and R2 are each aikyl containing not 9. 'y-Dimethyiaminopropyl benzhydryl eth r.

more than four carbon atoms. 10 GEORGE RIEVESCHL, Jn. 

